dbPTM

MP2K6_HUMAN - PTM Information in dbPTM

Basic Information of Protein

Overview of Protein Modification Sites with Functional and Structural Information
UniProt ID	MP2K6_HUMAN
UniProt AC	P52564
Protein Name	Dual specificity mitogen-activated protein kinase kinase 6
Gene Name	MAP2K6
Organism	Homo sapiens (Human).
Sequence Length	334
Subcellular Localization	Nucleus . Cytoplasm . Cytoplasm, cytoskeleton . Binds to microtubules.
Protein Description	Dual specificity protein kinase which acts as an essential component of the MAP kinase signal transduction pathway. With MAP3K3/MKK3, catalyzes the concomitant phosphorylation of a threonine and a tyrosine residue in the MAP kinases p38 MAPK11, MAPK12, MAPK13 and MAPK14 and plays an important role in the regulation of cellular responses to cytokines and all kinds of stresses. Especially, MAP2K3/MKK3 and MAP2K6/MKK6 are both essential for the activation of MAPK11 and MAPK13 induced by environmental stress, whereas MAP2K6/MKK6 is the major MAPK11 activator in response to TNF. MAP2K6/MKK6 also phosphorylates and activates PAK6. The p38 MAP kinase signal transduction pathway leads to direct activation of transcription factors. Nuclear targets of p38 MAP kinase include the transcription factors ATF2 and ELK1. Within the p38 MAPK signal transduction pathway, MAP3K6/MKK6 mediates phosphorylation of STAT4 through MAPK14 activation, and is therefore required for STAT4 activation and STAT4-regulated gene expression in response to IL-12 stimulation. The pathway is also crucial for IL-6-induced SOCS3 expression and down-regulation of IL-6-mediated gene induction; and for IFNG-dependent gene transcription. Has a role in osteoclast differentiation through NF-kappa-B transactivation by TNFSF11, and in endochondral ossification and since SOX9 is another likely downstream target of the p38 MAPK pathway. MAP2K6/MKK6 mediates apoptotic cell death in thymocytes. Acts also as a regulator for melanocytes dendricity, through the modulation of Rho family GTPases..
Protein Sequence	MSQSKGKKRNPGLKIPKEAFEQPQTSSTPPRDLDSKACISIGNQNFEVKADDLEPIMELGRGAYGVVEKMRHVPSGQIMAVKRIRATVNSQEQKRLLMDLDISMRTVDCPFTVTFYGALFREGDVWICMELMDTSLDKFYKQVIDKGQTIPEDILGKIAVSIVKALEHLHSKLSVIHRDVKPSNVLINALGQVKMCDFGISGYLVDSVAKTIDAGCKPYMAPERINPELNQKGYSVKSDIWSLGITMIELAILRFPYDSWGTPFQQLKQVVEEPSPQLPADKFSAEFVDFTSQCLKKNSKERPTYPELMQHPFFTLHESKGTDVASFVKLILGD

Experimental Post-Translational Modification Sites

* ASA = Accessible Surface Area

Locations	Modification	Substrate Peptides & Secondary Structure	ASA (%)	Reference
2	O-linked_Glycosylation	------MSQSKGKKR ------CCCCCCCCC	43.06	30379171
5	Acetylation	---MSQSKGKKRNPG ---CCCCCCCCCCCC	68.09	7692015
8	Acetylation	MSQSKGKKRNPGLKI CCCCCCCCCCCCCCC	67.10	7692023
14	Acetylation	KKRNPGLKIPKEAFE CCCCCCCCCCHHHHC	63.98	25953088
25	Phosphorylation	EAFEQPQTSSTPPRD HHHCCCCCCCCCCCC	31.18	23401153
26	Phosphorylation	AFEQPQTSSTPPRDL HHCCCCCCCCCCCCC	27.28	23401153
27	Phosphorylation	FEQPQTSSTPPRDLD HCCCCCCCCCCCCCC	48.60	29255136
28	Phosphorylation	EQPQTSSTPPRDLDS CCCCCCCCCCCCCCC	36.76	19664994
35	Phosphorylation	TPPRDLDSKACISIG CCCCCCCCCEEEEEC	29.47	22167270
36	Ubiquitination	PPRDLDSKACISIGN CCCCCCCCEEEEECC	47.12	-
40	Phosphorylation	LDSKACISIGNQNFE CCCCEEEEECCCCEE	25.07	28555341
57	Sulfoxidation	ADDLEPIMELGRGAY HHHCHHHHHHCCCCH	5.21	21406390
64	Phosphorylation	MELGRGAYGVVEKMR HHHCCCCHHHHHHHC	17.18	-
69	Ubiquitination	GAYGVVEKMRHVPSG CCHHHHHHHCCCCCC	29.62	-
82	Ubiquitination	SGQIMAVKRIRATVN CCCEEEEEEEEEECC	32.35	-
82	Acetylation	SGQIMAVKRIRATVN CCCEEEEEEEEEECC	32.35	7822209
90	Phosphorylation	RIRATVNSQEQKRLL EEEEECCHHHHHHHH	30.66	-
94	Ubiquitination	TVNSQEQKRLLMDLD ECCHHHHHHHHHHCC	44.24	-
116 (in isoform 2)	Ubiquitination	-	7.66	21890473
141	Methylation	TSLDKFYKQVIDKGQ CCHHHHHHHHHHCCC	41.02	115973075
141	Ubiquitination	TSLDKFYKQVIDKGQ CCHHHHHHHHHHCCC	41.02	-
146	Ubiquitination	FYKQVIDKGQTIPED HHHHHHHCCCCCCHH	41.62	-
172 (in isoform 1)	Ubiquitination	-	33.75	21890473
172	Acetylation	ALEHLHSKLSVIHRD HHHHHHHHHHHHCCC	33.75	-
172	Ubiquitination	ALEHLHSKLSVIHRD HHHHHHHHHHHHCCC	33.75	-
196	Glutathionylation	ALGQVKMCDFGISGY CCCCCCCCCCCCCCE	3.04	22555962
201	Phosphorylation	KMCDFGISGYLVDSV CCCCCCCCCEEHHHH	23.05	22322096
203	Phosphorylation	CDFGISGYLVDSVAK CCCCCCCEEHHHHHH	9.21	23403867
207	Phosphorylation	ISGYLVDSVAKTIDA CCCEEHHHHHHHHCC	19.25	22322096
207	Acetylation	ISGYLVDSVAKTIDA CCCEEHHHHHHHHCC	19.25	8651201
210	Acetylation	YLVDSVAKTIDAGCK EEHHHHHHHHCCCCC	43.80	17881352
211	Acetylation	LVDSVAKTIDAGCKP EHHHHHHHHCCCCCC	17.85	8622669
211	Phosphorylation	LVDSVAKTIDAGCKP EHHHHHHHHCCCCCC	17.85	22322096
219	Phosphorylation	IDAGCKPYMAPERIN HCCCCCCCCCCCCCC	7.45	-
232	Ubiquitination	INPELNQKGYSVKSD CCHHHHHCCCCCHHH	59.76	-
268	Sumoylation	GTPFQQLKQVVEEPS CCHHHHHHHHHHCCC	36.39	-
282	Ubiquitination	SPQLPADKFSAEFVD CCCCCHHHHHHHHHH	43.24	-
296	Ubiquitination	DFTSQCLKKNSKERP HHHHHHHHHCCCCCC	58.49	-
329	Sumoylation	TDVASFVKLILGD-- CCHHHHHHHHHCC--	28.00	-

Upstream regulatory proteins (kinases for phosphorylation sites, E3 ubiquitin ligases of ubiquitination sites, ...)

Modified Location	Modified Residue	Modification	Type of Upstream Proteins	Gene Name of Upstream Proteins	UniProt AC of Upstream Proteins	Sources
207	S	Phosphorylation	Kinase	MAP3K5	Q99683	GPS
207	S	Phosphorylation	Kinase	MAP3K7	O43318	GPS
207	S	Phosphorylation	Kinase	MAP3K8	P41279	GPS
207	S	Phosphorylation	Kinase	MAP2K6	P52564	GPS
207	S	Phosphorylation	Kinase	MAP3K-FAMILY	-	GPS
207	S	Phosphorylation	Kinase	MAP3K	-	Uniprot
211	T	Phosphorylation	Kinase	MAP3K7	O43318	GPS
211	T	Phosphorylation	Kinase	MAP3K-FAMILY	-	GPS
211	T	Phosphorylation	Kinase	MAP3K	-	Uniprot
219	Y	Phosphorylation	Kinase	MAP2K6	P52564	GPS
-	K	Ubiquitination	E3 ubiquitin ligase	FBXO31	Q5XUX0	PMID:24936062

Functions of PTM Sites

Modified Location	Modified Residue	Modification	Reference
207	S	Acetylation	16728640
(Microbial infection) Acetylation of Ser-207 and Thr-211 by Yersinia YopJ prevents phosphorylation and activation, thus blocking the MAPK signaling pathway.
207	S	Phosphorylation	16728640
(Microbial infection) Acetylation of Ser-207 and Thr-211 by Yersinia YopJ prevents phosphorylation and activation, thus blocking the MAPK signaling pathway.
207	S	Phosphorylation	16728640
Phosphorylated at Ser-207 and Thr-211 by the majority of M3Ks, such as MAP3K5/ASK1, MAP3K1/MEKK1, MAP3K2/MEKK2, MAP3K3/MEKK3, MAP3K4/MEKK4, MAP3K7/TAK1, MAP3K11/MLK3 and MAP3K17/TAOK2.
211	T	Acetylation	16728640
(Microbial infection) Acetylation of Ser-207 and Thr-211 by Yersinia YopJ prevents phosphorylation and activation, thus blocking the MAPK signaling pathway.
211	T	Phosphorylation	16728640
(Microbial infection) Acetylation of Ser-207 and Thr-211 by Yersinia YopJ prevents phosphorylation and activation, thus blocking the MAPK signaling pathway.
211	T	Phosphorylation	16728640
Phosphorylated at Ser-207 and Thr-211 by the majority of M3Ks, such as MAP3K5/ASK1, MAP3K1/MEKK1, MAP3K2/MEKK2, MAP3K3/MEKK3, MAP3K4/MEKK4, MAP3K7/TAK1, MAP3K11/MLK3 and MAP3K17/TAOK2.

Disease-associated PTM Sites based on SAP

* Distance = the distance between SAP position and PTM sites.

Modified Location	Modification	Variant Position (Distance <= 10)	Residue Change	SAP	Related Disease	Reference
Oops, there are no SNP-PTM records of MP2K6_HUMAN !!

Protein-Protein Interaction

Interacting Protein	Gene Name	Interaction Type	PPI Reference
MK14_HUMAN	MAPK14	physical	12697810
MK14_HUMAN	MAPK14	physical	8622669
MK14_HUMAN	MAPK14	physical	8626699
MK14_HUMAN	MAPK14	physical	11279118
M3K4_HUMAN	MAP3K4	physical	15866172
M3K5_HUMAN	MAP3K5	physical	15866172
MP2K4_HUMAN	MAP2K4	physical	15866172
MK14_HUMAN	MAPK14	physical	9808624
M3K7_HUMAN	MAP3K7	physical	12556533
MK14_HUMAN	MAPK14	physical	17255097
MAPK2_HUMAN	MAPKAPK2	physical	17255097
FBX31_HUMAN	FBXO31	physical	24936062
MK01_HUMAN	MAPK1	physical	10512765
MP2K3_HUMAN	MAP2K3	physical	26186194
ZG16B_HUMAN	ZG16B	physical	26186194
M3K4_HUMAN	MAP3K4	physical	25241761
GA45A_HUMAN	GADD45A	physical	25241761
TAOK2_HUMAN	TAOK2	physical	25241761
TF65_HUMAN	RELA	physical	25241761
RACK1_HUMAN	GNB2L1	physical	26038599
MP2K3_HUMAN	MAP2K3	physical	28514442
CYTN_HUMAN	CST1	physical	28514442

Drug and Disease Associations

Kegg Disease
There are no disease associations of PTM sites.
OMIM Disease
There are no disease associations of PTM sites.
Kegg Drug
There are no disease associations of PTM sites.
DrugBank
There are no disease associations of PTM sites.

Regulatory Network of MP2K6_HUMAN

Related Literatures of Post-Translational Modification

Acetylation
Reference	PubMed
"Lysine acetylation targets protein complexes and co-regulates majorcellular functions."; Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M., Walther T.,Olsen J.V., Mann M.; Science 325:834-840(2009). Cited for: ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-82, AND MASS SPECTROMETRY.	19608861 [Abstract]
Phosphorylation
Reference	PubMed
"Large-scale proteomics analysis of the human kinome."; Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G.,Mann M., Daub H.; Mol. Cell. Proteomics 8:1751-1764(2009). Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-27; THR-28 AND SER-207,AND MASS SPECTROMETRY.	19369195 [Abstract]
"Yersinia YopJ acetylates and inhibits kinase activation by blockingphosphorylation."; Mukherjee S., Keitany G., Li Y., Wang Y., Ball H.L., Goldsmith E.J.,Orth K.; Science 312:1211-1214(2006). Cited for: ACETYLATION AT SER-207 AND THR-211, PHOSPHORYLATION AT SER-207 ANDTHR-211, INACTIVATION BY YERSINIA YOPJ, AND MASS SPECTROMETRY.	16728640 [Abstract]
"Kinase-selective enrichment enables quantitative phosphoproteomics ofthe kinome across the cell cycle."; Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R.,Greff Z., Keri G., Stemmann O., Mann M.; Mol. Cell 31:438-448(2008). Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-28, AND MASSSPECTROMETRY.	18691976 [Abstract]

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